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Neo-adjuvant chemotherapy alone or with regional hyperthermia for soft-tissue sarcoma – Authors' reply
Correspondence
Neo-adjuvant chemotherapy alone or with regional hyperthermia for soft-tissue sarcoma Authors’ reply
Sergey Roussakow comments on four issues of our trial:1 bias caused by imbalanced post-induction chemo therapy application between study groups, subgroup-based analysis of the study endpoints, unreliable evaluation of tumour response, and an overall outcome worse than expected. Regarding the first comment, postinduction chemotherapy is driven by the result during induction therapy. Progress or death during induction therapy implies no post-induction chemotherapy. Induction therapy was balanced between both study groups: 151 (89%) of 169 patients in the hyperthermia group received four cycles compared with 146 (85%) of 172 in the control group (8% vs 12% received 1–3 cycles, and 2% vs 3% received no induction therapy). 37 (22%) of 172 in the control group compared with 15 (9%) of 169 in the hyperthermia group were not eligible for post-induction chemotherapy because of previous progression or death. The second comment, regarding information bias, overlooks the fact that all endpoints were evaluated on the complete sample size of 341 patients who were randomly allocated. In his third point, Roussakow questions the reliability of the study’s response evaluation. Overall response, which was two-to-three times greater in the hyperthermia group than in the control group (p=0·002), was confirmed independently by the masked European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group. This procedure was a measure taken against overestimation of objective www.thelancet.com/oncology Vol 18 October 2017
response to induction therapy. Finally, the population of our trial is of higher risk (majority of non-extremity tumours) in the neo-adjuvant setting compared with the populations included by the Sarcoma Metaanalysis Collaboration.2 In conclusion, Roussakow’s arguments are not serious objections against the scientific credibility of our 2010 study.1 Meanwhile, the results3,4 of the study’s long-term follow-up confirmed improved overall survival for patients treated with hyperthermia compared with those who were not. RDI has received personal fees from Pyrexar, PharmaMar, Bayer, and MedTherm. LHL has received grants from Dr Sennewald Medizintechnik GmbH; and personal fees from EL Medconsult GmbH, PharmaMar, Lilly, Eisai, and Novartis. RW and UM declares no competing interests.
*Rolf D Issels, Lars H Lindner, Rüdiger Wessalowski, Ulrich Mansmann [email protected] Department of Medicine III, University Hospital, Ludwig-Maximilians-University Munich, 81377 Munich, Germany (RDI, LHL); Clinic of Paediatric Oncology, Haematology and Immunology, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany (RW); and Department of Medical Information Sciences, Biometry, and Epidemiology, Ludwig-Maximilians-University Munich, Munich, Germany (UM) 1
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Issels RD, Lindner LH, Verweij J, et al; European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group (EORTC-STBSG); European Society for Hyperthermic Oncology (ESHO). Neo-adjuvant chemotherapy alone or with regional hyperthermia for localised high-risk soft-tissue sarcoma: a randomised phase 3 multicentre study. Lancet Oncol 2010; 11: 561–70. Sarcoma Meta-analysis Collaboration. Adjuvant chemotherapy for localised resectable soft-tissue sarcoma of adults: meta-analysis of individual data. Lancet 1997; 350: 1647–54. Issels RD, Lindner LH. Regional hyperthermia for high-risk soft tissue sarcoma treatment: present status and next questions. Curr Opin Oncol 2016; 28: 447–52. Issels RD, Lindner LH, Ghadjar P, et al. 13LBA improved overall survival by adding regional hyperthermia to neo-adjuvant chemotherapy in patients with localized high-risk soft tissue sarcoma (HR-STS): long-term outcomes of the EORTC 62961/ESHO randomized phase III study. Eur J Cancer Care 2015; 51 (suppl 3): S716.
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Neo-adjuvant chemotherapy alone or with regional hyperthermia for soft-tissue sarcoma Authors’ reply
Sergey Roussakow comments on four issues of our trial:1 bias caused by imbalanced post-induction chemo therapy application between study groups, subgroup-based analysis of the study endpoints, unreliable evaluation of tumour response, and an overall outcome worse than expected. Regarding the first comment, postinduction chemotherapy is driven by the result during induction therapy. Progress or death during induction therapy implies no post-induction chemotherapy. Induction therapy was balanced between both study groups: 151 (89%) of 169 patients in the hyperthermia group received four cycles compared with 146 (85%) of 172 in the control group (8% vs 12% received 1–3 cycles, and 2% vs 3% received no induction therapy). 37 (22%) of 172 in the control group compared with 15 (9%) of 169 in the hyperthermia group were not eligible for post-induction chemotherapy because of previous progression or death. The second comment, regarding information bias, overlooks the fact that all endpoints were evaluated on the complete sample size of 341 patients who were randomly allocated. In his third point, Roussakow questions the reliability of the study’s response evaluation. Overall response, which was two-to-three times greater in the hyperthermia group than in the control group (p=0·002), was confirmed independently by the masked European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group. This procedure was a measure taken against overestimation of objective www.thelancet.com/oncology Vol 18 October 2017
response to induction therapy. Finally, the population of our trial is of higher risk (majority of non-extremity tumours) in the neo-adjuvant setting compared with the populations included by the Sarcoma Metaanalysis Collaboration.2 In conclusion, Roussakow’s arguments are not serious objections against the scientific credibility of our 2010 study.1 Meanwhile, the results3,4 of the study’s long-term follow-up confirmed improved overall survival for patients treated with hyperthermia compared with those who were not. RDI has received personal fees from Pyrexar, PharmaMar, Bayer, and MedTherm. LHL has received grants from Dr Sennewald Medizintechnik GmbH; and personal fees from EL Medconsult GmbH, PharmaMar, Lilly, Eisai, and Novartis. RW and UM declares no competing interests.
*Rolf D Issels, Lars H Lindner, Rüdiger Wessalowski, Ulrich Mansmann [email protected] Department of Medicine III, University Hospital, Ludwig-Maximilians-University Munich, 81377 Munich, Germany (RDI, LHL); Clinic of Paediatric Oncology, Haematology and Immunology, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany (RW); and Department of Medical Information Sciences, Biometry, and Epidemiology, Ludwig-Maximilians-University Munich, Munich, Germany (UM) 1
2
3
4
Issels RD, Lindner LH, Verweij J, et al; European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group (EORTC-STBSG); European Society for Hyperthermic Oncology (ESHO). Neo-adjuvant chemotherapy alone or with regional hyperthermia for localised high-risk soft-tissue sarcoma: a randomised phase 3 multicentre study. Lancet Oncol 2010; 11: 561–70. Sarcoma Meta-analysis Collaboration. Adjuvant chemotherapy for localised resectable soft-tissue sarcoma of adults: meta-analysis of individual data. Lancet 1997; 350: 1647–54. Issels RD, Lindner LH. Regional hyperthermia for high-risk soft tissue sarcoma treatment: present status and next questions. Curr Opin Oncol 2016; 28: 447–52. Issels RD, Lindner LH, Ghadjar P, et al. 13LBA improved overall survival by adding regional hyperthermia to neo-adjuvant chemotherapy in patients with localized high-risk soft tissue sarcoma (HR-STS): long-term outcomes of the EORTC 62961/ESHO randomized phase III study. Eur J Cancer Care 2015; 51 (suppl 3): S716.
e630